ABSTRACT
The synthesis and structure activity relationship development of a pyrimidine series of heterocyclic Factor IXa inhibitors is described. Increased selectivity over Factor Xa inhibition was achieved through SAR expansion of the P1 element. Select compounds were evaluated in vivo to assess their plasma levels in rat.
Subject(s)
Drug Discovery , Factor IXa/antagonists & inhibitors , Factor Xa Inhibitors/pharmacology , Pyrimidines/pharmacology , Dose-Response Relationship, Drug , Factor IXa/metabolism , Factor Xa Inhibitors/chemical synthesis , Factor Xa Inhibitors/chemistry , Humans , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to MK-8718.
ABSTRACT
The synthesis and hit-to-lead SAR development from a pyrazolo[1,5-a]pyrimidine-derived hit 5 to the identification of a series of potent, pan-Pim inhibitors such as 11j are described.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Pyrimidines/chemistry , Pyrimidines/pharmacology , Humans , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-pim-1/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
The preparation of an indole appended vinamidinium salt, an indole appended vinylogous amide and an indole appended chloroenal are described. The subsequent regiospecific conversion of these indole containing building blocks to functionalized pyrazoles and pyrroles is detailed.
ABSTRACT
Previous efforts by our group have established pyrazolo[1,5-a]pyrimidine as a viable core for the development of potent and selective CDK inhibitors. As part of an effort to utilize the pyrazolo[1,5-a]pyrimidine core as a template for the design and synthesis of potent and selective kinase inhibitors, we focused on a key regulator in the cell cycle progression, CHK1. Continued SAR development of the pyrazolo[1,5-a]pyrimidine core at the C5 and C6 positions, in conjunction with previously disclosed SAR at the C3 and C7 positions, led to the discovery of potent and selective CHK1 inhibitors.
